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ANCA = antineutrophil cytoplasmic antibody; cANCA = cytoplasmic antineutrophil cytoplasmic antibody; CSS = Churg–Strauss syndrome; ICU =
intensive care unit; MPA = microscopic polyangiitis; MPO = myeloperoxidase; NPV = negative predictive value; PAN = polyarteritis nodosa;
pANCA = perinuclear antineutrophil cytoplasmic antibody; PPV = positive predictive value; PR = proteinase; WG = Wegener’s granulomatosis.
Critical Care February 2005 Vol 9 No 1 Semple et al.
Introduction
Systemic necrotizing vasculitis represents a major challenge
in critical care units. The prognosis of a fulminating vasculitic
illness is poor. For example, patients admitted to the intensive
care unit (ICU) with suspected pulmonary vasculitis have a
mortality of 25–50% [1]. Early and accurate diagnosis and
aggressive treatment are essential to improving outcome
while avoiding unnecessary immunosuppressive therapy. The
first presentation to the ICU may be with respiratory failure
and nonspecific changes on the chest radiograph rather than
the more classical renal failure. In a series of 26 patients
admitted to the ICU with systemic necrotizing vasculitis, the
initial diagnosis of vasculitis was made in the ICU in 42% of
cases [2]. It is therefore essential that vasculitis is included in
the differential diagnosis of unexplained pulmonary or renal
failure.
The clinical manifestations of the vasculitides are diverse, and
this is reflected in the manner of their presentation to the ICU.
Typically, this involves the lungs or kidneys, or both, although
the heart, central nervous system and gastrointestinal tract
can also all be involved. The most common conditions are
Wegener’s granulomatosis (WG), microscopic polyangiitis
(MPA), Churg–Strauss syndrome (CSS) and polyarteritis
nodosa (PAN). We explore the diagnosis of these entities in
the setting of the ICU and discuss their treatment, with an
emphasis on the role of the ICU. Detailed discussion of more

benign manifestations and the prolonged clinical course and
treatment can be found elsewhere [3–8].
Diagnosis
The conditions discussed here are uncommon. The
prevalences of WG, MPA, CSS and PAN have been quoted as
Review
Clinical review: Vasculitis on the intensive care unit – part 1:
diagnosis
David Semple
1
, James Keogh
2
, Luigi Forni
3
and Richard Venn
4
1
Specialist Registrar Renal Medicine, Worthing Hospital, Worthing, UK
2
Specialist Registrar Anaesthetics, Worthing Hospital, Worthing, UK
3
Consultant Physician, Worthing Hospital, Worthing, UK
4
Consultant Anaesthetist, Worthing Hospital, Worthing, UK
Corresponding author: David Semple,
Published online: 18 August 2004 Critical Care 2005, 9:92-97 (DOI 10.1186/cc2936)
This article is online at />© 2004 BioMed Central Ltd
Abstract
The first part of this review addresses the diagnosis and differential diagnosis of the primary vasculitides
Wegener’s granulomatosis, microscopic polyangiitis, Churg–Strauss syndrome and polyarteritis

nodosa. Prompt diagnosis and treatment of these conditions ensures an optimal prognosis. The
development of assays for antineutrophil cytoplasmic antibodies has aided the diagnosis of Wegener’s
granulomatosis and microscopic polyangiitis. However, even in cases where there is high clinical
likelihood that these conditions are present, up to 20% may be antibody negative, whereas alternative
diagnoses may be antibody positive. The final diagnosis rests on a balance of clinical, laboratory,
radiological and histological features. The exclusion of alternative diagnoses is important in assuring
appropriate therapy. Particular attention is paid to the more fulminant presentations of these conditions
and the role of the critical care physician in their diagnosis and management.
Keywords antineutrophil cytoplasmic antibody, critical care, Churg–Strauss syndrome, diagnosis, microscopic
polyangiitis, polyarteritis nodosa, vasculitis, Wegener’s granulomatosis
93
Available online />23, 25, 10, and 30 cases per million adult population,
respectively [9]. Other, more common diseases may share their
key clinical features, and therefore the clinician must have a
high index of suspicion in order to diagnose these conditions.
Although specific vasculitides do have their ‘classical’
symptoms, such as the temporal headache of giant cell
arteritis, the vasculitides liable to present in the ICU are less
definable. Despite this, clues in the clinical picture may aid
diagnosis (Table 1). Although the vasculitides may mimic an
infective process, in retrospect it may be apparent that the
clinical course is atypical, often with an extended,
generalized, nonspecific, prodromal illness in which repeated
courses of antibiotics have failed to produce the expected
improvement [10]. Careful enquiry may reveal multiorgan
involvement that had previously been overlooked. Table 2
gives the approximate frequencies of organ involvement in the
vasculitides considered in this review.
Attention to the past medical history may highlight associated
conditions, such as hepatitis (associated with PAN) as well

as, of course, a past history of vasculitis. It is worth noting
that asthma associated with CSS can precede the vasculitic
phase by up to 10 years.
The general examination may reveal subtle evidence of the
vasculitic process: nail-fold infarcts and splinter haemor-
rhages, retinal haemorrhages and Roth spots (which are not
just seen in bacterial endocarditis), scleritis and episcleritis,
palpable purpura and other less classical rashes, absent
pulses or bruits (indications of large vessel involvement), and
oral ulceration.
Pointers to a possible vasculitis may be found in the bedside
and ‘routine’ laboratory investigations. The temperature chart
will typically show a persistent low-grade pyrexia, while new
onset hypertension may be a marker of undiagnosed renal
involvement, particularly in PAN. Urinalysis must be
performed. Is the patient being treated for urinary sepsis on
the basis of blood and protein on the urine dipstick in the
absence of leucocytes and/or nitrites? Could this be
evidence of glomerulonephritis instead? Unexplained hypoxia
may indicate subclinical pulmonary haemorrhage, often
identified in retrospect once the diagnosis is apparent.
Normocytic anaemia, neutrophil leucocytosis, and a raised
erythrocyte sedimentation rate and capsular reactive protein
are typical findings, but they add little in determining the
specific diagnosis. The urea and creatinine can vary
enormously, and premorbid values are particularly important
in interpreting these findings. Blood and protein identified on
the bedside urinalysis should prompt urine microscopy. The
chest radiograph can range from normal to showing evidence
of florid pulmonary haemorrhage or multiple cavitating

lesions. However, it more commonly shows a non-
discriminatory patchy alveolar infiltration.
The American College of Rheumatology produced
classification criteria for WG, CSS and PAN in patients with
a confirmed vasculitis [11–15]. These are not diagnostic
criteria. These classification criteria have sensitivities and
specificities for distinguishing vasculitides between 80% and
90% [13–15]. They are intended to classify confirmed
vasculitides (principally for research purposes) and are not
intended to differentiate vasculitic from nonvasculitic
disorders [12]. Furthermore, they do not recognize the
diagnosis of MPA; patients with this disorder are classified as
having WG. Their positive predictive value (PPV) for
diagnosing WG or PAN in patients only suspected of having
a vasculitis may be as low as 17–25%, making them
unsuitable diagnostic criteria [16].
Antineutrophil cytoplasmic antibody-
associated small vessel vasculitides
Wegener’s granulomatosis/microscopic polyangiitis
WG and MPA are often grouped together as the antineutrophil
cytoplasmic antibody (ANCA)-associated small vessel vasculi-
tides. However, up to 10% of these cases will be ANCA
negative [17]. They can affect many organ systems, and
clinically are differentiated by their predilection for the pulmonary
system (Table 2). No single test is capable of diagnosing or
distinguishing between these conditions. Therefore, a
combination of clinical, serological and histopathological
factors must be considered to provide a final diagnosis.
Clinical features
WG is a granulomatous vasculitis that, in contrast to CSS,

does not cause asthma, although the two may coexist
because of the prevalence of asthma in the population. Nasal,
Table 1
Summary of common presenting features
Disease
Presenting features WG MPA CSS PAN
Constitutional upset ++ ++ ++ ++
Sinusitis +++ + +++ +
Asthma – – +++ –
SOB/cough +++ + ++ +
Rash + + ++ +
Abdominal pain + + + ++
Hypertension + + + ++
Proteinuria/haematuria +++ +++ ++ –
Cardiac failure/pericarditis + + ++ +
Mononeuritis (multiplex) + + ++ ++
CSS, Churg–Strauss syndrome; MPA, microscopic polyangiitis; PAN,
polyarteritis nodosa; SOB, shortness of breath; WG, Wegener’s
granulomatosis.
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Critical Care February 2005 Vol 9 No 1 Semple et al.
oropharyngeal, or pulmonary involvement is essentially
universal at diagnosis. Ear, nose and throat disease includes
epistaxis, nasal and oral ulceration and necrosis, sinus pain
and hearing loss. Pulmonary involvement includes
haemorrhage, pleural effusions and large airway inflammation
and stenosis. Pulmonary haemorrhage may be extensive
before haemoptysis or other overt clinical signs become
apparent. Renal involvement ranges from a subclinical
glomerulonephritis (blood and protein on the urine bedside

test) to rapidly progressive glomerulonephritis, and it is nearly
universal [18]. A respiratory limited form of the diseases has
been touted, but over 80% of these cases go on to develop
renal disease, and so the distinction is of little use [19]. The
presence of renal disease is arbitrarily used to define
generalized.
MPA is a nongranulomatous vasculitis that has less of a
predilection for the lungs, although pulmonary involvement is
still seen in up to 40% of cases [20]. Renal involvement is
again common.
Cardiac involvement can occur in both, manifesting as
myocarditis, coronary arteritis, valvulitis, endocarditis,
conduction disturbances and pericarditis. Acute pericardial
inflammation may lead to life threatening tamponade [21].
The musculoskeletal, neurological and cutaneous systems
are also frequently affected, in WG more than in MPA.
Antineutrophil cytoplasmic antibodies
Particularly important in both the diagnosis and pathogenesis
of the small vessel vasculitides is the ANCA. Indirect
immunofluorescence identifies two clinically important patterns
of staining: cytoplasmic ANCA (cANCA) and perinuclear
ANCA (pANCA). In WG and MPA, these are directed against
specific constituents of neutrophil granules, namely the
antigens proteinase (PR)-3 and myleoperoxidase (MPO),
respectively. In practice this is demonstrated by an enzyme-
linked immunosorbent assay. Binding of ANCAs to these
molecules on activated neutrophils is felt to be an important
mechanism of tissue injury in vasculitis. The sensitivities and
specificities of these assays are shown in Table 3.
There is some crossover of cANCAs and pANCAs between

WG and MPA. pANCAs directed against MPO are found in
up to 24% of WG cases, whereas up to 27% of MPA cases
will be cANCA positive [22]. Pragmatically, because
distinguishing WG from MPA does not change therapy in the
ICU, it is only necessary to identify the presence of a small
vessel vasculitis and not to classify it. By using testing with
both indirect immunofluorescence and enzyme-linked
immunosorbent assay for the combination of cANCA and
PR-3 or pANCA and MPO, the sensitivity for diagnosing the
presence of either WG or MPA can be increased to
approximately 73%, while the specificity remains at
approximately 99% [22]. However, the presence or absence
of ANCAs cannot be used in isolation to diagnose or exclude
WG or MPA. Other conditions may also produce a positive
ANCA (up to 50% of CSS patients will give a positive result
for PR-3 or MPO [22]), and other antigens can produce a
similar staining pattern (especially the pANCA). Furthermore,
the PPV and negative predictive value (NPV) of any
diagnostic test depend on the prevalence of the disease in
the population being investigated. ANCA has the highest
PPV and the lowest NPV in patients who have the most
classical clinical presentation, but neither value ever reaches
100%; a negative result, while decreasing the likelihood of
the diagnosis, never excludes it. For example, when
Table 2
Approximate frequencies (%) of major organ involvement
Organ system WG MPA CSS PAN
Skin 50 40 60 50
Renal 80 90 60–80 30
Pulmonary 90 50 40

a
Rare
Ear, nose and throat 90 35 50 Uncommon
Musculoskeletal 60 60 50 50–60
Neurological 30 30 70 60–70
b
GI tract 50 50 50 30
Cardiac 10 20–40 20–30
a
Evidence of pulmonary vasculitis; excludes asthma.
b
Predominantly
mononeuritis multiplex. CSS, Churg–Strauss syndrome; MPA,
microscopic polyangiitis; PAN, polyarteritis nodosa; WG, Wegener’s
granulomatosis. Data compiled from [3,18,20,26,28].
Table 3
Approximate sensitivity and specificity of antineutrophil
cytoplasmic antibody in detecting primary vasculitides
Sensitivity Specificity
(%) (%)
WG
cANCA 64 95
PR-3 66 87
PR-3 + ANCA 55 99
MPA
pANCA 58 81
MPO 58 91
MPO + ANCA 49 99
WG or MPA
PR-3 + cANCA or MPO + pANCA 67–73 99

cANCA, cytoplasmic antineutrophil cytoplasmic antibody; MPA,
microscopic polyangiitis; MPO, myeloperoxidase; pANCA, perinuclear
antineutrophil cytoplasmic antibody; PR, proteinase; WG, Wegener’s
granulomatosis. Data from Hagen and coworkers [22].
95
attempting to diagnosis renal vasculitis in the context of
significant renal impairment and other clinical features
consistent with WG or MPA, the presence or absence of
pANCA–MPO or cANCA–PR-3 combinations have a PPV of
92–98% and a NPV of 80–93% [23]. Therefore, a negative
ANCA still leaves a likelihood of up to a 20% that such a
patient has a small vessel vasculitis.
Imaging
Radiological techniques can be used to help confirm the
involvement of multiple organs in the disease process, but
there are few features that are specific to WG or MPA alone.
Granulomata, pulmonary infiltrates, or haemorrhage can be
identified on chest radiography or, with more sensitivity, on
high-resolution computed tomography. However, there are
many other conditions (e.g. tuberculosis, sarcoidosis and
malignancy) that can mimic these changes. Their presence
adds to the overall picture but should not be interpreted in
isolation. A computed tomography scan of the sinuses may
be more helpful, especially in WG, in which a mucosal
thickening, bony destruction and infiltration to the orbits can
all suggest WG [24].
Histology
Where possible, biopsy of an affected organ is desirable.
Skin biopsy shows a leucocytoclastic vasculitis, which
confirms the presence of a vasculitic process, but it is also

seen in many conditions other than MPA and WG.
Nasopharyngeal biopsy is useful if lesions are present and
may provide diagnostic information for WG if granulomatous
disease is identified. However, relatively small amounts of
tissue are often obtained and only one-third of biopsies show
features distinguishable as active vasculitis.
When no easily accessible lesions are present, then a
decision on the next most appropriate site for biopsy must be
made based on the clinical picture. Renal biopsy shows a
segmental necrotizing cresentic glomerulonephritis, with no
immunoglobulin deposition (so called ‘pauci-immune’). This
contrasts with other causes of cresentic glomerulonephritis,
such as bacterial endocarditis or the collagen vascular
diseases, which have immunoglobulin deposited in the
glomerulus. Although diagnostic of a primary small vessel
vasculitis, this histological picture rarely distinguishes WG
from MPA because granulomas are seen infrequently. Lung
biopsy reveals a granulomatous inflammation and vasculitis.
Open or thoroscopic biopsy has a far higher diagnostic yield
(up to 90% if specific lesions can be identified) than
transbronchial biopsy, which provides diagnostic material in
only 10% of cases.
Churg–Strauss syndrome
The hallmarks of CSS are asthma (95%), allergic rhinitis
(55–70%), a peripheral blood eosinophilia (>1.5 × 10
9
/l or
>10% of total white cell count) and evidence of a systemic
vasculitis affecting two or more extrapulmonary organs.
Particularly important is cardiac involvement (acute

pericarditis, constrictive pericarditis, heart failure and
myocardial infarction), which accounts for up to 50% of
deaths attributable to CSS [7,25].
Clinical features
Characteristically, the asthma precedes the vasculitic phase
of the illness by up to 2–3 decades, although the two can
appear simultaneously. Often this is problematic enough to
warrant long-term steroids, which can have the effect of
masking the development of future systemic features. As well
as asthma, allergic rhinitis and skin lesions (tender
subcutaneous nodules on the extensor surfaces, palpable
purpura, haemorrhagic lesions or a maculopapular rash) are
exceedingly common (Table 2).
Renal disease is more common than originally appreciated,
with up to 84% of patients in one series of 19 patients
exhibiting some degree of renal involvement, ranging from
subclinical proteinuria to renal failure [26]. However, renal
failure requiring replacement therapy is still relatively rare
(around 10% of cases).
Other investigations
There is no diagnostic laboratory test. A marked peripheral
eosinophilia is the most common finding, but it is not specific.
Furthermore, this can fluctuate rapidly, particularly in
response to treatment, and can therefore easily be missed if
steroids are started for the asthma before investigations are
performed. IgE levels are also typically elevated, and there are
circulating immune complexes. pANCA is positive against
MPO, as in MPA, in around 50% of cases [7].
Imaging
Chest radiographic features can be very diverse, ranging from

transient patchy opacities to the widespread shadowing of
pulmonary haemorrhage. High-resolution computed tomo-
graphy is more useful, and the findings of enlargement of the
peripheral pulmonary arteries and alterations in their
configuration may help to support the diagnosis.
Histology
Open or thoroscopic lung biopsy is again more useful than
transbronchial biopsy. Alternatively, sural nerve biopsy, in
patients with evidence of a polyneuritis, may be helpful. Renal
biopsy typically shows the nondiagnostic features of a focal
segmental glomerulonephritis, and extravascular eosinophilic
granulomas are rarely seen [26]. As such, renal biopsy adds
little to the diagnosis that could not have been predicted from
urine microscopy and analysis.
Polyarteritis nodosa
PAN is a necrotizing vasculitis of the medium and small
muscular vessels, which may affect any organ system.
Historically it has often been considered part of a spectrum of
disease involving MPA and CSS. However, it is now clear
Available online />96
that these are discrete conditions. In a subgroup of patients
with PAN the disease process seems related to active
hepatitis B infection. Clinically, this is indistinguishable from
idiopathic PAN; however, the treatment strategies are quite
different [27]. For this reason, testing for hepatitis B should
be conducted early in the disease course.
Clinical features
The characteristic features of PAN can be appreciated from
the consequences of infarction and ischaemia in critical
organs because of the involvement of small and medium

sized arteries. This commonly presents as a syndrome of
multiorgan failure/compromise, on the background of
constitutional upset (e.g. fever, malaise, weight loss). This
may involve the nervous system, skin, kidneys and gastro-
intestinal tract, although any organ can be affected (Table 2).
Pulmonary involvement is documented, but this is far less
common than in the other vasculitides. Cardiac involvement
occurs in only about 10–30% of cases [28] but can produce
significant compromise.
Nerve involvement typically takes the form of mononeuritis
multiplex, with both sensory and motor components. This can
be present in up to 65% of cases [28] and, in the absence of
diabetes, is highly suggestive of PAN. Central nervous
system involvement is increasingly recognized. Most
commonly, this takes the form of stroke (either ischaemic or
haemorrhagic) or cranial nerve palsies, due to necrosis and
narrowing of medium sized intracranial vessels.
Renal involvement is clinically significant in up to 50% of
cases [28], but it is even more commonly found at autopsy.
Narrowing of renal vessels leads to multiple areas of renal
infarction, glomerular ischaemia and hypertension. A true
glomerulonephritis is not typically found, and so the urine is
frequently normal (unlike in WG, MPA and CSS).
Gastrointestinal tract involvement is heralded by abdominal
pain, which may worsen after meals (abdominal angina). The
spectrum then continues to include haemorrhage, infarction
and perforation.
Imaging
In most vasculitides imaging techniques are of little value in
diagnosis, but this is not the case for PAN. Angiography of

either the gastrointestinal tract or kidneys characteristically
shows multiple aneurysms and irregular constriction of the
large vessels and occlusion of the penetrating vessels. This is
often considered diagnostic in the correct clinical setting,
making it possible to avoid the need to obtain a tissue
diagnosis from a potentially very sick patient.
Histology
A tissue biopsy is still the ‘gold standard’ diagnostic test, and
affected areas will show the classical necrotic inflammation of
the medium sized arteries, which is diagnostic of PAN.
Differential diagnosis
Excluding alternative diagnoses is as important as positively
identifying a vasculitis. Exactly what this involves will depend to
a large degree on the clinical picture and the potential mimics
are legion. However, the principal alternative diagnoses include
infection, immune-mediated conditions such as thrombotic
thrombocytopaenic purpura and cryoglobulinaemia, malignancy
and the collagen vascular diseases (Table 4).
Infection
Distinguishing infection from vasculitis is of paramount
importance. Close liaison with microbiology is essential.
Persistently negative microbiological assays, in the context of
an inflammatory illness, increase the possibility that a
vasculitis is present. Bacterial endocarditis, if suspected,
requires multiple blood cultures at different times.
Complement levels can be helpful, tending to be low in
immune complex diseases (including cryoglobulinaemia) but
normal or elevated in primary systemic vasculitis. The blood
film is helpful in identifying microangiopathic haemolysis
associated with disseminated intravascular coagulation,

haemolytic–uraemic syndrome and thrombocytopaenic
thrombotic purpura, all of which may mimic vasculitis.
Consideration must also be given to the patient being treated
Critical Care February 2005 Vol 9 No 1 Semple et al.
Table 4
Common differential diagnoses
Differential diagnosis Examples
Infection Overwhelming sepsis (e.g.
meningococcal sepsis)
Atypical pneumonia
Legionella infection
Lyme’s disease
Leptospirosis
Tuberculosis
Bacterial endocarditis
Mycotic aneurysms
Haemolytic–uraemic syndrome
Collagen vascular disease Systemic lupus erythematosus
Rheumatoid arthritis
Antiphospholipid syndrome
Sjögren’s syndrome
Cryoglobulinaemia
Malignancy Lymphoma/leukaemia
Paraneoplastic syndromes
Other Sarcoid
Thrombotic thrombocytopenic purpura
Cholesterol emboli
97
in the ICU. Unfortunately, nosocomial infections are likely to
occur. Surveillance should always be borne in mind.

Collagen vascular disease
The collagen vascular diseases often require serological
differentiation from primary vasculitis. Antinuclear, double-
stranded DNA, antiphospholipid antibodies, rheumatoid
factor and extractable nuclear antigen antibodies should be
tested for. Again, complement levels may be low. Cryo-
globulinaemia, sometimes associated with rheumatoid arthritis
(and hepatitis C), requires careful investigation if suspected.
Malignancy
Malignancy can mimic vasculitis either through bone marrow
suppression or paramalignant processes. These para-
malignant syndromes do not tend to produce florid organ
failure, and so they are unlikely to be the cause of a patient’s
admission to critical care.
Conclusion
The vasculitides remain an important diagnostic challenge to
the critical care physician. Their presentation remains diverse
and closely resembles other, more common conditions. They
require prompt diagnosis if significant permanent organ
damage is to be avoided, but no single reliable test exists to
readily and reliably confirm or exclude their presence.
Furthermore, in those cases in which the disease is severe
enough to warrant admission to ICU, approximately 50% may
be undiagnosed.
The final diagnosis requires a high index of suspicion, careful
compilation of all the clinical, laboratory, radiological and
histological evidence available, and exclusion of important
alternative diagnoses.
The second part of this review will consider treatment of
these conditions, giving emphasis to the role of the ICU,

before going on the discuss their prognosis.
Competing interests
The author(s) declare that they have no competing interests.
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